Cystic fibrosis (CF), the most common semilethal hereditary disease among Caucasians, is manifested as a generalized dysfunction of exocrine glands. Mucous secretions throughout the body are abnormal in CF, but the subcellular defect underlying this abnormality is not understood. My goals are to determine first, whether intestinal glycoprotein-secreting cells of CF patients respond to extracellular secretagogues and inhibitors in the same way as do their counterparts in normal individuals and second, whether CF mucous cells, when stimulated to secrete, carry out exocytosis in a normal fashion. Glycoprotein transport and secretion in rectal goblet and columnar cells will be studied in laboratory animals and in human rectal biopsies, both normal and CF, maintained in organ culture. The effects of representative secretagogues and inhibitors on the intracellular movement and release of radioactively-labeled glycoproteins will be assessed by autoradiography. The interaction, fusion and fission of intracellular membranes which accompany modulation of exocytosis in goblet cells will be investigated in detail by freeze-fracture and electron microscopy. My preliminary freeze-fracture studies on human rectal goblet cells revealed the presence of uniquely extensive and long-lived membrane interactions in these cells. Further study of these interactions under conditions of secretory stimulation and inhibition may help to clarify our concepts of membrane events in normal exocytosis. Through systematic comparison of autoradiographic, freeze-fracture and ultrastructural data from normal and CF mucous cells, I hope to establish whether the CF genetic defect leads to alterations in the regulation of secretion or in the membranes involve in exocytosis.